COMPARATIVE GENOMICS OF PARASITIC NEMATODES

寄生线虫的比较基因组学

基本信息

批准号：
9285732
负责人：
Makedonka Mitreva
金额：
$ 38.07万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-23 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9285732
关键词：
Anthelmintics Automobile Driving Basic Science Behavior Biochemical Pathway Biological Assay Buffers Communities Data Data Analyses Databases Development Diagnostic Drug Targeting Drug resistance Enzyme Inhibition Enzyme Inhibitor Drugs Enzymes Evolution Generations Genome Genomics Goals Growth and Development function Hookworms Human In Vitro Infection Intervention Intestines Laboratories Lead Maintenance Massachusetts Medical Metabolic Metabolic Pathway Metabolism Mining Molecular Monitor Morbidity - disease rate Nature Nematoda Outcome Parasite Control Parasites Parasitic nematode Parasitology Pharmaceutical Preparations Phylogenetic Analysis Post-Translational Protein Processing Poverty Predictive Value Property Proteins Protocols documentation Research Resources Sequence Analysis Structure Systems Biology Taxonomy Testing Time Universities Vaccines Validation Virulence Washington analog base burden of illness cheminformatics comparative genomics data access differential expression drug development drug sensitivity filaria human morbidity improved in vivo innovation interdisciplinary approach knowledge base medical schools metabolic abnormality assessment metabolomics molecular sequence database mortality multidisciplinary mutant novel novel diagnostics novel therapeutics parasitism pathogen pharmacophore public health priorities public health relevance reconstruction research and development tool transcriptome transcriptomics

项目摘要

DESCRIPTION (provided by applicant): Parasitic nematodes infect more than two billion people, causing significant morbidity and mortality. Characterization of the genomes of parasitic nematode provides fundamental molecular information that can be used to accelerate basic research and the development of new diagnostics and therapeutics, which are a public health priority due to the limited number of currently available drugs, the limited efficacy against some species (e.g., whipworm) and increasing anti-drug resistance. To that end, we have established an extensive genomic database by sequencing and annotating genomes and transcriptomes of nematode parasites of medical importance, including representative human parasites that span the major taxonomic clades in the phylum Nematoda. Furthermore, we focused analysis on biochemical pathways conserved and/or taxonomically restricted and condition-specific, identifying proteins that may prove useful as drug targets. The three aims of this proposal build on our progress by taking advantage of the generated multi-dimensional resource to undertake a systems biology approach aimed at promoting discovery and development of new therapeutics. First, we will reconstruct metabolic networks of both intestinal and filarial parasits, and analysis will focus on pan-conserved chokepoint enzymes in taxonomically restricted and differentially expressed metabolic pathways as potential targets for anthelmintic drugs. Second, we will perform drug-sensitivity assays to test our hypothesis and validate the predicted broad control potential of the pan-phylum targets. Third, we will perform lead optimization and demonstrate increased potency and selectivity of nematode metabolic enzyme inhibitors, followed by validation of target inhibition in vitro and in vivo. Keys to our overall approach include the selection of species of parasites that span the evolutionary extremes of the Phylum (supporting the creation of a pan-phylum metabolic pathway database with the broadest scope and optimal predictive value), the development of a prioritization protocol that leverages systems biology and cheminformatics for target and drug prioritization, followed by experimental validation and, in turn, identification and optimization of leads. The expected outcome will facilitate and promote the discovery and development of novel interventions to treat and control these important parasites and reduce their associated morbidity and mortality.

描述（由申请人提供）：寄生线虫感染超过 20 亿人，导致显着的发病率和死亡率。寄生线虫基因组的表征提供了可用于加速基础研究和新诊断和治疗方法开发的基本分子信息。由于目前可用的药物数量有限，对某些物种（例如鞭虫）的疗效有限，并且抗药性不断增加，因此这是一个公共卫生优先事项。通过对具有医学重要性的线虫寄生虫的基因组和转录组进行测序和注释，建立了一个广泛的基因组数据库，包括跨越线虫门主要分类分支的代表性人类寄生虫。此外，我们重点分析了保守和/或分类学限制和条件的生化途径。该提案的三个目标建立在我们利用生成的多维资源进行旨在促进发现和开发的系统生物学方法的进展的基础上。首先，我们将重建肠道和丝虫寄生虫的代谢网络，分析将集中于分类学限制和差异表达的代谢途径中的泛保守阻塞点酶，作为驱虫药物的潜在靶点。敏感性测定来检验我们的假设并验证泛门目标的预测广泛控制潜力。第三，我们将进行先导化合物优化并证明线虫代谢酶抑制剂的效力和选择性有所提高。我们整体方法的关键包括选择跨越门进化极限的寄生虫物种（支持创建具有最广泛范围和预测最佳值的泛门代谢途径数据库。），开发优先方案，利用系统生物学和化学信息学进行靶标和药物优先排序，然后进行实验验证，进而识别和优化先导化合物，预期结果将促进和促进新型干预措施的发现和开发。治疗和控制这些重要的寄生虫并降低其相关的发病率和死亡率。